Is RINT1 p.Ala458= (c.1374T>C) pathogenic?

RINT1 p.Ala458= (c.1374T>C) is classified Benign in RINT1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 8.41%, amr) — too common for a highly-penetrant pathogenic allele.

RINT1 p.Ala458=

Q: How common is RINT1 p.Ala458= (c.1374T>C) in the general population?

RINT1 p.Ala458= (c.1374T>C) is common (popmax 8.41%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1374T>C · rs35961194 · VCV224930

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 8.41%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 2, phastCons 1
Overall
CADD	11.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.41% Admixed American · 4,989/59,352 alleles

Filtering AF 8.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.13%

Overall 1.66% 26,786/1,609,958 alleles · common exomes 24,638/1,457,630 · genomes 2,148/152,328 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	8.41%	12
European (non-Finnish)	1.67%	60
Remaining individualsnot grpmax-eligible	1.29%	78
Finnishnot grpmax-eligible	1.02%	98
Ashkenazi Jewishnot grpmax-eligible	0.481%	208
African / African-American	0.342%	293
South Asian	0.321%	311
Amishnot grpmax-eligible	0.219%	456
Middle Eastern	0.198%	504
East Asian	0.00447%	22,364

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RINT1
Protein: p.Ala458=
Coding: c.1374T>C
MANE Select: NM_021930
dbSNP: rs35961194
Type: single nucleotide variant
Location: chr7:105551610 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.97
Residue 458: the rint1/tip20 domain

Full RINT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RINT1 p.Ala458Pro Uncertain significance ★ ⚠ same residue
RINT1 p.Ala458Ser Uncertain significance ★ ⚠ same residue
RINT1 p.Ala458Val Uncertain significance ★ ⚠ same residue
RINT1 c.1107+1G>T Likely pathogenic ★★ same type
RINT1 c.1886+5G>A Uncertain significance ★★ same type
RINT1 c.516-3C>T Uncertain significance ★★ same type
RINT1 c.840-12T>A Uncertain significance ★★ same type
RINT1 c.840-3C>G Uncertain significance ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rint1-p-ala458 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown